Abstract The goal of this project is to identify novel genes involved in human retinal disorders, a stated priority of the National Eye Institute. To accomplish this, additional genes whose mutations cause Leber congenital amaurosis (LCA), the most common hereditary cause of visual impairment in infants and children, will be identified by combining whole exome sequencing with genetic mapping. Mutations in known LCA genes account for about 63% of all cases in the European population, suggesting that many additional LCA genes remain to be identified. To identify additional LCA disease genes, we have collected 37 consanguineous families with recessive LCA from Saudi Arabia. Homozygosity mapping and known LCA disease gene sequencing suggests that 18 of these families carry novel mutations in multiple novel LCA disease loci. In addition, we have sequenced all 16 known LCA genes in a collection of over 600 patient samples and have identified 224 unrelated patients that likely carry mutations in novel LCA disease genes. Therefore, this collection represents a well characterized, rich resource for identifying new genes that can cause LCA. In this proposal, we will identify the underlying mutations in these patients using a combination of whole exome sequencing, bioinformatics, statistics, and functional studies. Our Specific Aims are to: 1. Perform positional cloning of disease genes in consanguineous LCA families 2. Identify novel LCA genes by whole exome sequencing of a 300-patient cohort 3. Continued enrollment and mutation analysis of LCA families Discovery of novel LCA genes will assist the development of new diagnostic tools and treatments. In addition, since mutations in LCA disease genes also cause other retinal dystrophies, isolation of additional LCA disease genes will provide important insights into the molecular mechanisms underlying both LCA and retinal dystrophies in general. PUBLIC HEALTH RELEVANCE: Description The goal of this research project is to use cutting edge genomic sequencing technology to identify novel genes that are involved in human Leber congenital amaurosis (LCA), the most common hereditary cause of visual impairment in infants and children. Currently, the cause of disease in about 35% of LCA patients remains unknown. Identification of novel LCA genes will provide the basis for accurate diagnosis as well as developing new treatment methods for the disease.